CN108586364A - A kind of Dibenzazepines compound and the preparation method and application thereof - Google Patents
A kind of Dibenzazepines compound and the preparation method and application thereof Download PDFInfo
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- CN108586364A CN108586364A CN201711462414.6A CN201711462414A CN108586364A CN 108586364 A CN108586364 A CN 108586364A CN 201711462414 A CN201711462414 A CN 201711462414A CN 108586364 A CN108586364 A CN 108586364A
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- 0 C*C(Cc1c*(C*)ccc1NC(C=C*C*)=*(C)*)=O Chemical compound C*C(Cc1c*(C*)ccc1NC(C=C*C*)=*(C)*)=O 0.000 description 8
- ZQLWPDINFATPCT-UHFFFAOYSA-N Cc(ccc(-c(cc1)ccc1F)c1)c1C(Nc1ccccc1N)=O Chemical compound Cc(ccc(-c(cc1)ccc1F)c1)c1C(Nc1ccccc1N)=O ZQLWPDINFATPCT-UHFFFAOYSA-N 0.000 description 1
- HVIJPUNIJITRMG-UHFFFAOYSA-N O=C1NC(CCC=CC2)=C2Nc2c1cccc2 Chemical compound O=C1NC(CCC=CC2)=C2Nc2c1cccc2 HVIJPUNIJITRMG-UHFFFAOYSA-N 0.000 description 1
- BZMXNMGZYPMQGA-UHFFFAOYSA-N O=Cc1cc(-c(cc2)cc3c2Nc2ccccc2NC3=O)ccc1 Chemical compound O=Cc1cc(-c(cc2)cc3c2Nc2ccccc2NC3=O)ccc1 BZMXNMGZYPMQGA-UHFFFAOYSA-N 0.000 description 1
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of Dibenzazepines compounds and the preparation method and application thereof.The structure of the Dibenzazepines compound is as shown in general formula 1 or general formula 2, wherein R1Selected from methyl, hydrogen, chlorine or bromine, R2Selected from methyl or hydrogen, R3Selected from hydrogen, chlorine atom, bromine atom, the phenyl for replacing or being unsubstituted, naphthalene or pyridine；The hydrogen that is substituted by phenyl ortho position or meta or para position is each independently by one or more substitutions in fluorine, chlorine, methyl, methoxyl group, itrile group or trifluoromethyl.Dibenzazepines compound of the present invention has significant cancer cell suppression activity, especially has significant inhibitory activity to human breast cancer cell, gastric carcinoma cells, human liver cancer cell, human cervical carcinoma cell, human acute myeloid leukaemia.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of Dibenzazepines compound and preparation method thereof with answer
With.
Background technology
Tumour is a kind of most common, most serious disease that the world today directly jeopardizes human life, it refers to that body exists
Under the effect of various tumorigenesis factors, the cell paraplasm of local organization and the local lump that is formed, wherein malignant tumour are also known as cancer
Disease.The annual whole world has million people to die of cancer, accounts for the 12% of death toll；According to 08 year Ministry of Public Health's statistical report, China was in recent years
Number of cancer deaths average annual 1500000, account for the 25% of death toll, and have increased trend year by year.After cardiovascular and cerebrovascular disease,
Cancer has become the second largest disease for threatening China human mortality health.
Benzodiazepines compound also has application in medicine, for example as anxiolytic drugs, antiarrhythmic drug,
Vasopressin antagonists, hiv reverse transcriptase inhibitor and cholecystokinin antagonist.Chinese patent (publication number：
CN103435562A a kind of 6- substitutions Benzodiazepine -2,4- cyclohexadione compounds) are disclosed, has to cancer cell and inhibits to live
Property.
The compound of molecular skeleton structure containing Dibenzazepine has multiple biological activities.The application design has synthesized one
The novel Dibenzazepines compound of series structure finds that such compound has good antitumor activity by studying, because
This has quotability in anti-tumor aspect, can develop into the new superior drug for cancer, and is further derivatization
The drug molecule of research and pharmacological research structure containing Dibenzazepine is laid a good foundation.
Invention content
The purpose of the present invention is to provide a kind of novel Dibenzazepines compounds, and prepare the side of such compound
Method and application in preparation of anti-tumor drugs.
Dibenzazepines compound provided by the present invention has the structure as shown in general formula 1 or general formula 2：
Wherein, R1Selected from methyl, hydrogen, chlorine or bromine, R2Selected from methyl or hydrogen；
R3Selected from hydrogen, chlorine, bromine, the phenyl for replacing or being unsubstituted, naphthalene or pyridine；Hydrogen on the substituted phenyl is respectively
Independently by one or more substitutions in fluorine, chlorine, methyl, methoxyl group, itrile group or trifluoromethyl.
Wherein, compound shown in general formula 1 is to prepare the midbody compound of compound shown in general formula 2.
Dibenzazepines compound of the present invention has significant cancer cell suppression activity.
Preferably, R1For hydrogen or bromine, R2For hydrogen；
R3For bromine, substituted phenyl, naphthalene or pyridine；The hydrogen being substituted by phenyl is each independently by fluorine, chlorine, methyl
Or one or more substitutions in trifluoromethyl.
Preferably, R1For hydrogen or bromine, R2For hydrogen；
R3For bromine, substituted phenyl or naphthalene；The hydrogen being substituted by phenyl contraposition is each independently by methyl or trifluoro
One or both of methyl replaces.
Preferably, compound shown in ideal general formula 1 includes, but are not limited to following compound：
Preferably, compound shown in ideal general formula 2 includes, but are not limited to following compound：
Preferably, structure shown in the general formula 2 is selected from compound shown in 4a, 12a, 16a, 17a, 18a, 19a, 20a, 21a.
Wherein, compound 4a, 18a, 19a, 20a, 21a is thin to human breast cancer cell, gastric carcinoma cells, human liver cancer cell, human cervical carcinoma
Born of the same parents, human acute myeloid leukaemia all have good inhibiting effect；Compound 12a, 16a, 17a are thin to human breast carcinoma
Born of the same parents, gastric carcinoma cells, human acute myeloid leukaemia all have good inhibiting effect.
Dibenzazepines compound of the present invention can be prepared by this field conventional technical means, in order to more
Good obtains Dibenzazepines compound, and the present invention also provides the preparation methods of Dibenzazepines compound：
It the preparation course of compound shown in general formula 1 and is as follows：
(1) using o-iodobenzoic acid as raw material, with absolute ethyl alcohol occur esterification obtain o-iodobenzoic acid ethyl ester, then not with
O-phenylenediamine or 3,4- dimethyl o-phenylenediamines carry out the graceful reaction in Wall and obtain compound 1 or 2 respectively；
Or further：
(2) it is raw material with compound 1, carry out electrophilic substitution reaction with N- bromo-succinimides or two chlordantoins gives birth to respectively
At compound 3 or 4-6；Wherein, in the compound 3-6, R1Selected from hydrogen, chlorine or bromine, R3For chlorine or bromine；
Compound 4-6 described above includes, but is not limited to following compound：
Or further：
(3) it is raw material with compound 3, by itself and R3-(BOH)2It carries out Suzuki reactions and generates compound 7-23 respectively；Institute
It states in compound 7-23, R3For the phenyl, naphthalene or pyridine for replacing or being unsubstituted；The hydrogen being substituted by phenyl is respectively independent
Ground is by one or more substitutions in fluorine, chlorine, methyl, methoxyl group, itrile group or trifluoromethyl；
Compound 7-23 described above includes, but is not limited to following compound：
Popular response item known in the art may be used in above-mentioned preparation method of the present invention, step (1)-(3)
Part is to realize above-mentioned reaction.
Further, in order to improve the quality of synthetic route, the present invention is made that the reaction condition of each step following excellent
Choosing limits：
In step (1), the molar ratio of the preferably described o-iodobenzoic acid ethyl ester and the o-phenylenediamine is 1-3:1 (more preferably
It is 2:1)；The molar ratio of the o-iodobenzoic acid ethyl ester and the 3,4- dimethyl o-phenylenediamine is 1-3:1 (more preferably 2:
1)；
In addition, the graceful reaction in Wall described in step (1) carries out in a solvent under the effect of the catalyst, the catalyst is
Cuprous iodide and potassium phosphate；The solvent is preferably ethylene glycol；
Further, the reaction temperature of the graceful reaction in the Wall is 150-210 DEG C, and the reaction time is 0.5-1 hours.
In step (2), the compound 1 is 1 with the molar ratio of the N- bromo-succinimides or two chlordantoins:1-
1.2, more preferably 1:1.1；
In addition, electrophilic substitution reaction described in step (2) preferably carries out in n,N-Dimethylformamide or tetrahydrofuran；
Further, the reaction temperature of the electrophilic substitution reaction is -5-5 DEG C, and the reaction time is 2-4 hours.
In step (3), the molar ratio of the compound 3 and described phenyl boric acid or derivatives thereof is 1:1-2；The compound
3 with the molar ratio of the pyridine boronic acid be 1:1-2；The pyridine boronic acid is preferably 3- pyridine boronic acids or 4- pyridine boronic acids；
In addition, the reactions of Suzuki described in step (3) carry out in a solvent under the effect of the catalyst, the catalyst is
Potassium carbonate, tetrakis triphenylphosphine palladium or two (triphenylphosphine) palladium chlorides；The solvent is preferably by toluene：Ethyl alcohol：Water=3-
5:1.5-2.5:1 (preferably 4:2:Or N,N-dimethylformamide 1)：Water=0.5-1.5:1 (preferably 1:1) mixing formed is molten
Agent；
Further, it is preferable to which the reaction temperature of the Suzuki reactions is 80-130 DEG C；Reaction time is 4-12 hours.
The preparation course of compound shown in general formula 2 is as follows：
Specially：Compound shown in general formula 1 carries out chlorination with phosphorus oxychloride and generates imino group chloride, by gained Asia
Imino chloride carries out substitution reaction with excessive N methyl piperazine and obtains compound shown in general formula 2.
Above-mentioned chlorination carries out in reaction dissolvent under the effect of the catalyst, and the catalyst is preferably N, N- diformazans
Base aniline；The reaction dissolvent is preferably phosphorus oxychloride.
Preferably, the molar ratio of compound and n,N-Dimethylaniline shown in the general formula 1 is 1:0.4-0.8, preferably
1:0.6；
It is further preferred that the reaction temperature of the chlorination is 120-140 DEG C, the reaction time is 20-28 hours.
The preparation method of above-mentioned Dibenzazepines compound provided by the present invention can further include to product
Separation and purification the step of, the conventional treatment of this field specifically can be used, the present invention is not particularly limited this.
The present invention also provides above-mentioned Dibenzazepines compounds (especially structure shown in general formula 2) to press down as cancer cell
The application of preparation.
Preferably, the cancer cell is breast cancer cell BCAP37, gastric carcinoma cells SGC7901, human liver cancer cell
HepG2, human cervical carcinoma cell HeLa or human acute myeloid leukaemia HL-60；Preferably breast cancer cell BCAP37, people
Gastric carcinoma cell line SGC-7901 or human acute myeloid leukaemia HL-60.
Invention further provides above-mentioned Dibenzazepines compounds (especially structure shown in general formula 2) to control in preparation
The application in cancer drug is treated, the cancer is preferably breast cancer, gastric cancer, liver cancer, cervical carcinoma or leukaemia；Preferably mammary gland
Cancer, gastric cancer or leukaemia.
The present invention provides a kind of completely new Dibenzazepines compound, and above compound cancer displays are gone out it is prominent
The therapeutic activity gone out can be effectively used for the treatment of cancer, especially have to breast cancer, gastric cancer, liver cancer, cervical carcinoma or leukaemia aobvious
The therapeutic activity of work.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
Embodiment 1：The preparation of compound 1
Weigh o-iodobenzoic acid ethyl ester 5.52g (20mmol) that o-iodobenzoic acid obtains after absolute ethyl alcohol is esterified and
1.08g (10mmol) o-phenylenediamines sequentially add cuprous iodide (190mg, 1mmol), potassium phosphate in microwave reaction pipe
(6.36g, 30mmol), proper amount of glycol and magneton carry out microwave reaction under 180 DEG C, nitrogen protection, stop reaction after 1h,
TLC detection reactions terminate.It is extracted with ethyl acetate (3 × 100mL), the salt water washing being saturated with water and in right amount is associated with
Anhydrous Na is added in machine layer2SO4Water removal, using filter, finally concentrates residual solution, pillar layer separation obtains 1.37g compounds 1, institute
The yield for obtaining compound 1 is 65%.
1H NMR (400MHz, DMSO) δ 9.85 (s, 1H), 7.85 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.33 (t,
J=7.2Hz, 1H), 7.02-6.86 (m, 6H).
Embodiment 2：The preparation of compound 2
The present embodiment is reacted in the same manner as shown in Example 1, is differed only in, with 3,4- dimethyl neighbour's benzene
Diamines replaces the o-phenylenediamine in embodiment 1, and the yield of gained compound 2 is 51%.
1H NMR(400MHz,DMSO)δ9.69(s,1H),7.67–7.60(m,2H),7.34–7.26(m,1H),6.95
(d, J=7.9Hz, 1H), 6.85 (t, J=7.5Hz, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 2.08 (d, J=5.6Hz,
6H).
Embodiment 3：The preparation of compound 3
Appropriate n,N-Dimethylformamide is added in 100ml round-bottomed flasks in Weigh Compound 1 (1.05g, 5mmol),
The N- bromo-succinimides (979mg, 5.5mmol) dissolved by a small amount of N,N-dimethylformamide are slowly added dropwise under 0 DEG C of stirring,
After reacting 2h, TLC detects raw material and largely disappears, and stops reaction.It is extracted with ethyl acetate (3 × 100mL), with water and is fitted
The salt water washing of saturation is measured, organic layer is merged, anhydrous Na is added2SO4Water removal, using filter, finally concentrates residual solution, column color
Spectrum detaches to obtain 864mg compounds 3, and the yield of gained compound 3 is 60%.
1H NMR (400MHz, DMSO) δ 9.97 (s, 1H), 8.04 (s, 1H), 7.74 (d, J=2.4Hz, 1H), 7.49
(dd, J=8.6,2.5Hz, 1H), 6.99-6.89 (m, 5H)
Embodiment 4：The preparation of compound 4
The present embodiment is reacted according to method same as Example 3, in addition to obtaining compound 3, while obtaining chemical combination
Object 4, wherein the yield of gained compound 4 is 10%.
1H NMR (400MHz, DMSO) δ 10.04 (s, 1H), 8.18 (s, 1H), 7.74 (d, J=2.4Hz, 1H), 7.51
(dd, J=8.6,2.5Hz, 1H), 7.17-7.09 (m, 2H), 6.92 (dd, J=8.4,4.3Hz, 2H)
Embodiment 5：The preparation of compound 5
The present embodiment is reacted according to method same as Example 3, is differed only in, and is replaced with two chlordantoins real
The N- bromo-succinimides in example 3 are applied, and the N in embodiment 3, N- dimethyl formyls are replaced with reaction dissolvent tetrahydrofuran
The yield of amine, gained compound 5 is 60%.
1H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 8.03 (s, 1H), 7.61 (d, J=2.6Hz, 1H), 7.38
(dd, J=8.6,2.6Hz, 1H), 7.02-6.89 (m, 5H)
Embodiment 6：The preparation of compound 6
The present embodiment is reacted according to method same as Example 5, in addition to obtaining compound 5, while obtaining chemical combination
Object 6, wherein the yield of gained compound 6 is 10%.
1H NMR (400MHz, DMSO) δ 10.06 (s, 1H), 8.16 (s, 1H), 7.61 (d, J=2.6Hz, 1H), 7.39
(dd, J=8.6,2.7Hz, 1H), 7.03-6.96 (m, 4H)
Embodiment 7：The preparation of compound 7
Weigh Compound 3 (288mg, 1mmol) and phenyl boric acid (183mg, 1.5mmol) are in 50ml round-bottomed flasks, successively
Potassium carbonate (276mg, 2mmol), tetrakis triphenylphosphine palladium (58mg, 0.05mmol), suitable mixed solvent (toluene is added：Second
Alcohol：Water=4:2:1) and magneton, be stirred under 80 DEG C, nitrogen protection, after 12h TLC detections reaction terminates.Use ethyl acetate
(3 × 70mL) is extracted, and the salt water washing being saturated with water and in right amount merges organic layer, and anhydrous Na is added2SO4Water removal, then pass through
Filtering, finally concentrates residual solution, pillar layer separation obtains 226mg compounds 7, yield 79%.
1H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 7.99 (d, J=27.4Hz, 2H), 7.67 (d, J=7.6Hz,
1H), 7.58 (d, J=7.3Hz, 2H), 7.42 (t, J=7.2Hz, 2H), 7.31 (t, J=7.0Hz, 1H), 7.09 (d, J=
8.2Hz,1H),7.03–6.89(m,4H).
Embodiment 8：The preparation of compound 8
The present embodiment is reacted according to method same as Example 7, is differed only in, with 2- methylphenylboronic acid generations
For the phenyl boric acid in embodiment 7, the yield of gained compound 8 is 64%.
1H NMR (400MHz, DMSO) δ 9.87 (s, 1H), 7.95 (s, 1H), 7.78 (d, J=2.2Hz, 1H), 7.46
(dd, J=8.3,2.2Hz, 1H), 7.33-7.28 (m, 1H), 7.24 (dd, J=7.5,1.6Hz, 1H), 7.09-6.96 (m,
6H),6.95–6.89(m,1H),3.74(s,3H).
Embodiment 9：The preparation of compound 9
The present embodiment is reacted according to method same as Example 7, is differed only in, with 3- methylphenylboronic acid generations
For the phenyl boric acid in embodiment 7, the yield of gained compound 9 is 83%.
1H NMR (400MHz, DMSO) δ 9.93 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=2.3Hz, 1H), 7.67
(dd, J=8.4,2.3Hz, 1H), 7.34 (t, J=7.9Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 7.11-7.06 (m, 2H),
7.03–6.87(m,5H),3.80(s,3H).
Embodiment 10：The preparation of compound 10
The present embodiment is reacted according to method same as Example 7, is differed only in, with 4- methylphenylboronic acid generations
For the phenyl boric acid in embodiment 7, the yield of gained compound 10 is 86%.
1H NMR (400MHz, DMSO) δ 9.91 (s, 1H), 7.94 (s, 1H), 7.88 (d, J=2.3Hz, 1H), 7.61
(dd, J=8.4,2.3Hz, 1H), 7.52 (d, J=8.7Hz, 2H), 7.06 (d, J=8.4Hz, 1H), 7.02-6.88 (m, 6H),
3.77(s,3H).
Embodiment 11：The preparation of compound 11
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 2- fluorobenzoic boric acids
The yield of phenyl boric acid in embodiment 7, gained compound 11 is 70%.
1H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=8.4Hz,
1H), 7.48 (td, J=7.9,1.5Hz, 1H), 7.40-7.34 (m, 1H), 7.31-7.24 (m, 2H), 7.09 (d, J=8.4Hz,
1H),7.04–6.89(m,4H).
Embodiment 12：The preparation of compound 12
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 3- fluorobenzoic boric acids
The yield of phenyl boric acid in embodiment 7, gained compound 12 is 68%.
1H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.07 (s, 1H), 7.97 (d, J=2.1Hz, 1H), 7.70
(dd, J=8.4,2.2Hz, 1H), 7.51-7.39 (m, 3H), 7.17-7.06 (m, 2H), 7.04-6.89 (m, 4H)
Embodiment 13：The preparation of compound 13
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 4- fluorobenzoic boric acids
The yield of phenyl boric acid in embodiment 7, gained compound 13 is 70%.
1H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=2.3Hz, 1H), 7.68-
7.55 (m, 3H), 7.24 (t, J=8.8Hz, 2H), 7.08 (d, J=8.4Hz, 1H), 7.02 (dd, J=7.6,1.1Hz, 1H),
7.00–6.94(m,2H),6.94–6.88(m,1H).
Embodiment 14：The preparation of compound 14
The present embodiment is reacted according to method same as Example 7, is differed only in, with 3- itrile group phenyl boric acid generations
For the phenyl boric acid in embodiment 7, the yield of gained compound 14 is 71%.
1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.10 (d, J=10.1Hz, 2H), 8.00 (d, J=2.2Hz,
1H), 7.95 (d, J=8.1Hz, 1H), 7.82-7.72 (m, 2H), 7.63 (t, J=7.8Hz, 1H), 7.10 (d, J=8.5Hz,
1H),7.06–6.88(m,4H).
Embodiment 15：The preparation of compound 15
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 2- chlorophenylboronic acids
The yield of phenyl boric acid in embodiment 7, gained compound 15 is 80%.
1H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=2.2Hz, 1H), 7.53 (d,
J=7.3Hz, 1H), 7.43 (dd, J=8.3,2.3Hz, 1H), 7.41-7.33 (m, 3H), 7.08 (d, J=8.3Hz, 1H),
7.04–6.90(m,4H).
Embodiment 16：The preparation of compound 16
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 3- chlorophenylboronic acids
The yield of phenyl boric acid in embodiment 7, gained compound 16 is 71%.
1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.08 (s, 1H), 7.96 (d, J=2.3Hz, 1H), 7.70
(dd, J=8.4,2.4Hz, 1H), 7.63 (t, J=1.6Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 7.44 (t, J=7.9Hz,
1H), 7.36 (dd, J=8.0,0.9Hz, 1H), 7.09 (d, J=8.4Hz, 1H), 7.03-6.89 (m, 4H)
Embodiment 17：The preparation of compound 17
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 4- chlorophenylboronic acids
The yield of phenyl boric acid in embodiment 7, gained compound 17 is 63%.
1H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=2.3Hz, 1H), 7.67
(dd, J=8.4,2.3Hz, 1H), 7.61 (d, J=8.6Hz, 2H), 7.46 (d, J=8.5Hz, 2H), 7.09 (d, J=8.4Hz,
1H),7.03–6.89(m,4H).
Embodiment 18：The preparation of compound 18
The present embodiment is reacted according to method same as Example 7, is differed only in, with 4- trifluoromethylbenzene boron
Acid replaces the phenyl boric acid in embodiment 7, and the yield of gained compound 18 is 62%.
1H NMR(400MHz,DMSO)δ9.98(s,1H),8.15(s,1H),8.04(s,1H),7.86–7.70(m,5H),
7.12 (d, J=8.4Hz, 1H), 7.04-6.89 (m, 4H)
Embodiment 19：The preparation of compound 19
The present embodiment is reacted according to method same as Example 7, is differed only in, with 4- methylphenylboronic acid generations
For the phenyl boric acid in embodiment 7, the yield of gained compound 19 is 75%.
1H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 7.98 (s, 1H), 7.92 (d, J=2.3Hz, 1H), 7.64
(dd, J=8.4,2.1Hz, 1H), 7.48 (d, J=8.0Hz, 2H), 7.23 (d, J=8.0Hz, 2H), 7.07 (d, J=8.4Hz,
1H),7.03–6.89(m,4H),2.31(s,3H).
Embodiment 20：The preparation of compound 20
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 1- naphthalene boronic acids real
The phenyl boric acid in example 7 is applied, the yield of gained compound 20 is 89%.
1H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.08 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.92 (d,
J=8.2Hz, 1H), 7.82 (d, J=8.3Hz, 1H), 7.77 (d, J=2.2Hz, 1H), 7.58-7.46 (m, 4H), 7.40 (dd,
J=7.0,0.9Hz, 1H), 7.16 (d, J=8.3Hz, 1H), 7.07 (d, J=7.9Hz, 1H), 7.02-6.91 (m, 3H)
Embodiment 21：The preparation of compound 21
The present embodiment is reacted according to method same as Example 7, is differed only in, and is replaced with 2- naphthalene boronic acids real
The phenyl boric acid in example 7 is applied, the yield of gained compound 21 is 43%.
1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.15 (s, 1H), 8.12 (d, J=2.3Hz, 1H), 8.06 (s,
1H), 8.01-7.95 (m, 2H), 7.92 (d, J=7.5Hz, 1H), 7.84 (dd, J=8.4,2.4Hz, 1H), 7.79 (dd, J=
8.6,1.8Hz, 1H), 7.55-7.47 (m, 2H), 7.14 (d, J=8.4Hz, 1H), 7.03 (dd, J=7.6,1.4Hz, 1H),
7.01–6.95(m,2H),6.95–6.90(m,1H).
Embodiment 22：The preparation of compound 22
Weigh Compound 3 (288mg, 1mmol) and 3- pyridine boronic acids (184mg, 1.5mmol) in 50ml round-bottomed flasks,
Sequentially add potassium carbonate (276mg, 2mmol), two (triphenylphosphine) palladium chlorides (35mg, 0.05mmol), it is suitable mixing it is molten
Agent (N,N-dimethylformamide：Water=1:1) it and magneton, is stirred under 130 DEG C, nitrogen protection, TLC detections reaction after 4h
Terminate.It is extracted with ethyl acetate (3 × 70mL), the salt water washing being saturated with water and in right amount merges organic layer, is added anhydrous
Na2SO4Water removal, using filter, finally concentrates residual solution, pillar layer separation obtains 258mg compounds 22, yield 90%.
1H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 8.82 (d, J=2.1Hz, 1H), 8.51 (dd, J=4.7,
1.5Hz, 1H), 8.10 (s, 1H), 8.02-7.95 (m, 2H), 7.73 (dd, J=8.4,2.4Hz, 1H), 7.44 (dd, J=7.9,
4.8Hz, 1H), 7.12 (d, J=8.4Hz, 1H), 7.04-6.89 (m, 4H)
Embodiment 23：The preparation of compound 23
The present embodiment is reacted according to 22 identical method of embodiment, is differed only in, with 4- pyridine boronic acid generations
For the 3- pyridine boronic acids in embodiment 22, the yield of gained compound 23 is 78%.
1H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 8.57 (d, J=5.9Hz, 2H), 8.21 (s, 1H), 8.09 (d,
J=2.2Hz, 1H), 7.83-7.79 (m, 1H), 7.63 (d, J=6.0Hz, 2H), 7.12 (d, J=8.5Hz, 1H), 7.03-
6.90(m,4H).
Embodiment 24：The preparation of compound 1a
Weigh Compound 1 (105mg, 0.5mmol) sequentially adds n,N-Dimethylaniline in 50ml round-bottomed flasks
(36.3mg, 0.3mmol), suitable super dry phosphorus oxychloride and magneton, carry out return stirring, 12h under 130 DEG C, nitrogen protection
Extra phosphorus oxychloride is evaporated afterwards, appropriate N methyl piperazine is added and continues to stir, and TLC detections, which are reacted, after 12h terminates.Use acetic acid
Ethyl ester (3 × 70mL) is extracted, and the salt water washing being saturated with water and in right amount merges organic layer, and anhydrous Na is added2SO4Water removal,
Using filter, finally residual solution is concentrated, pillar layer separation (dichloromethane：Methanol=25:1) 110mg compound 1a, yield are obtained
It is 75%.
1H NMR(400MHz,CDCl3) δ 7.31-7.25 (m, 2H), 7.09 (dd, J=7.8,1.0Hz, 1H), 6.98 (dd,
J=15.5,7.8Hz, 2H), 6.88 (td, J=7.6,1.3Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.70 (d, J=
7.7Hz,1H),4.93(s,1H),3.47(s,4H),2.52(s,4H),2.35(s,3H).
Embodiment 25：The preparation of compound 2a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 2 real
The compound 1 in example 24 is applied, the yield of gained compound 2a is 51%.
1H NMR(400MHz,CDCl3) δ 7.28-7.21 (m, 2H), 6.95 (t, J=7.5Hz, 1H), 6.89 (s, 1H),
6.79 (d, J=7.9Hz, 1H), 6.48 (s, 1H), 4.85 (s, 1H), 3.43 (s, 4H), 2.50 (s, 4H), 2.34 (s, 3H),
2.12(s,6H).
Embodiment 26：The preparation of compound 3a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 3 real
The compound 1 in example 24 is applied, the yield of gained compound 3a is 43%.
1H NMR(400MHz,CDCl3) δ 7.37-7.32 (m, 2H), 7.05 (dd, J=7.8,1.4Hz, 1H), 6.96 (td,
J=7.6,1.4Hz, 1H), 6.86 (td, J=7.5,1.5Hz, 1H), 6.70-6.63 (m, 2H), 4.93 (s, 1H), 3.42 (s,
4H),2.50(s,4H),2.33(s,3H).
Embodiment 27：The preparation of compound 4a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 4 real
The compound 1 in example 24 is applied, the yield of gained compound 4a is 44%.
1H NMR(400MHz,CDCl3) δ 7.39-7.31 (m, 2H), 7.18 (d, J=2.2Hz, 1H), 6.93 (dd, J=
8.3,2.3Hz, 1H), 6.66 (d, J=8.2Hz, 1H), 6.51 (d, J=8.3Hz, 1H), 4.93 (s, 1H), 3.42 (s, 4H),
2.48(s,4H),2.31(s,3H).
Embodiment 28：The preparation of compound 5a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 5 real
The compound 1 in example 24 is applied, the yield of gained compound 5a is 33%.
1H NMR(400MHz,CDCl3) δ 7.26-7.21 (m, 2H), 7.08 (dd, J=7.8,1.2Hz, 1H), 6.98 (td,
J=7.6,1.2Hz, 1H), 6.89 (td, J=7.5,1.4Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.68 (dd, J=7.7,
1.1Hz,1H),4.93(s,1H),3.45(s,4H),2.53(s,4H),2.35(s,3H).
Embodiment 29：The preparation of compound 6a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 6 real
The compound 1 in example 24 is applied, the yield of gained compound 6a is 54%.
1H NMR(400MHz,CDCl3) δ 7.27-7.23 (m, 2H), 7.06 (d, J=2.3Hz, 1H), 6.83 (dd, J=
8.3,2.3Hz, 1H), 6.76 (d, J=8.3Hz, 1H), 6.60 (d, J=8.4Hz, 1H), 4.88 (s, 1H), 3.46 (s, 4H),
2.52(s,4H),2.35(s,3H).
Embodiment 30：The preparation of compound 7a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 7 real
The compound 1 in example 24 is applied, the yield of gained compound 7a is 29%.
1H NMR(400MHz,CDCl3) δ 7.54-7.44 (m, 4H), 7.41 (t, J=7.5Hz, 2H), 7.31 (t, J=
7.2Hz, 1H), 7.11 (d, J=7.7Hz, 1H), 6.98 (t, J=7.5Hz, 1H), 6.91-6.81 (m, 2H), 6.70 (d, J=
7.7Hz,1H),5.01(s,1H),3.50(s,4H),2.51(s,4H),2.33(s,3H).
Embodiment 31：The preparation of compound 8a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 8 real
The compound 1 in example 24 is applied, the yield of gained compound 8a is 30%.
1H NMR(400MHz,CDCl3) δ 7.45-7.38 (m, 2H), 7.29 (td, J=8.2,1.7Hz, 1H), 7.18 (dd,
J=7.5,1.7Hz, 1H), 7.08 (dd, J=7.8,1.4Hz, 1H), 7.01-6.93 (m, 3H), 6.87 (dd, J=7.6,
1.5Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 6.70 (dd, J=7.7,1.2Hz, 1H), 4.97 (s, 1H), 3.77 (s, 3H),
3.54(s,4H),2.51(s,4H),2.33(s,3H).
Embodiment 32：The preparation of compound 9a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 9 real
The compound 1 in example 24 is applied, the yield of gained compound 9a is 34%.
1H NMR(400MHz,CDCl3) δ 7.52-7.43 (m, 2H), 7.32 (t, J=7.9Hz, 1H), 7.10 (dd, J=
7.8,0.9Hz, 1H), 7.05 (d, J=7.7Hz, 1H), 7.01-6.93 (m, 2H), 6.91-6.83 (m, 3H), 6.70 (dd, J=
7.6,0.6Hz,1H),4.99(s,1H),3.83(s,3H),3.49(s,4H),2.51(s,4H),2.33(s,3H).
Embodiment 33：The preparation of compound 10a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 10
The yield of compound 1 in embodiment 24, gained compound 10a is 23%.
2-(4-methoxyphenyl)-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]
diazepine,Yellow jelly；1H NMR(400MHz,CDCl3) δ 7.47-7.34 (m, 4H), 7.09 (dd, J=7.8,
1.4Hz, 1H), 6.97 (dd, J=7.4,1.4Hz, 1H), 6.95-6.92 (m, 2H), 6.87 (dd, J=7.6,1.5Hz, 1H),
6.85-6.82 (m, 1H), 6.69 (dd, J=7.7,1.3Hz, 1H), 5.01 (s, 1H), 3.81 (s, 3H), 3.49 (s, 4H),
2.51(s,4H),2.32(s,3H).
Embodiment 34：The preparation of compound 11a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 11
The yield of compound 1 in embodiment 24, gained compound 11a is 35%.
1H NMR(400MHz,CDCl3) δ 7.49 (s, 1H), 7.43 (d, J=8.2Hz, 1H), 7.33-7.24 (m, 2H),
7.19-7.08 (m, 3H), 6.97 (td, J=7.6,1.2Hz, 1H), 6.94-6.82 (m, 2H), 6.70 (dd, J=7.7,
0.9Hz,1H),5.00(s,1H),3.50(s,4H),2.52(s,4H),2.33(s,3H).
Embodiment 35：The preparation of compound 12a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 12
The yield of compound 1 in embodiment 24, gained compound 12a is 14%.
1H NMR(400MHz,CDCl3) δ 7.49-7.44 (m, 2H), 7.39-7.32 (m, 1H), 7.23 (d, J=7.5Hz,
1H), 7.18-7.12 (m, 1H), 7.09 (dd, J=7.8,1.1Hz, 1H), 7.03-6.94 (m, 2H), 6.91-6.84 (m, 2H),
6.70 (dd, J=7.7,0.9Hz, 1H), 4.99 (s, 1H), 3.47 (s, 4H), 2.51 (s, 4H), 2.33 (s, 3H)
Embodiment 36：The preparation of compound 13a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 13
The yield of compound 1 in embodiment 24, gained compound 13a is 24%.
1H NMR(400MHz,CDCl3) δ 7.45-7.37 (m, 4H), 7.12-7.05 (m, 3H), 6.97 (td, J=7.6,
1.4Hz, 1H), 6.90-6.83 (m, 2H), 6.70 (dd, J=7.7,1.3Hz, 1H), 5.00 (s, 1H), 3.48 (s, 4H), 2.50
(s,4H),2.32(s,3H).
Embodiment 37：The preparation of compound 14a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 14
The yield of compound 1 in embodiment 24, gained compound 14a is 4.6%.
1H NMR(400MHz,CDCl3) δ 7.86-7.64 (m, 2H), 7.59 (d, J=7.7Hz, 1H), 7.52 (d, J=
7.8Hz, 1H), 7.49-7.42 (m, 2H), 7.09 (dd, J=7.8,1.2Hz, 1H), 6.98 (td, J=7.6,1.2Hz, 1H),
6.94-6.82 (m, 2H), 6.70 (dd, J=7.7,1.0Hz, 1H), 5.01 (s, 1H), 3.47 (s, 4H), 2.53 (s, 4H),
2.34(s,3H).
Embodiment 38：The preparation of compound 15a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 15
The yield of compound 1 in embodiment 24, gained compound 15a is 25%.
1H NMR(400MHz,CDCl3) δ 7.48-7.43 (m, 1H), 7.38 (d, J=2.1Hz, 1H), 7.31 (dd, J=
8.1,2.1Hz, 1H), 7.29-7.25 (m, 2H), 7.22-7.18 (m, 1H), 7.11 (dd, J=7.8,1.4Hz, 1H), 6.99
(td, J=7.6,1.4Hz, 1H), 6.91 (dd, J=7.6,1.5Hz, 1H), 6.87 (d, J=8.2Hz, 1H), 6.72 (dd, J=
7.7,1.3Hz,1H),5.03(s,1H),3.52(s,4H),2.52(s,4H),2.34(s,3H).
Embodiment 39：The preparation of compound 16a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 16
The yield of compound 1 in embodiment 24, gained compound 16a is 40%.
1H NMR(400MHz,CDCl3) δ 7.47-7.40 (m, 3H), 7.33-7.25 (m, 3H), 7.10 (dd, J=7.8,
1.4Hz, 1H), 6.97 (td, J=7.6,1.4Hz, 1H), 6.88 (dd, J=7.6,1.5Hz, 1H), 6.86-6.83 (m, 1H),
6.69 (dd, J=7.7,1.3Hz, 1H), 5.04 (s, 1H), 3.47 (s, 4H), 2.50 (s, 4H), 2.32 (s, 3H)
Embodiment 40：The preparation of compound 17a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 17
The yield of compound 1 in embodiment 24, gained compound 17a is 40%.
1H NMR(400MHz,CDCl3) δ 7.47-7.39 (m, 2H), 7.39-7.30 (m, 4H), 7.09 (dd, J=7.8,
1.4Hz, 1H), 6.97 (td, J=7.6,1.4Hz, 1H), 6.91-6.82 (m, 2H), 6.69 (dd, J=7.7,1.3Hz, 1H),
4.99(s,1H),3.47(s,4H),2.50(s,4H),2.33(s,3H).
Embodiment 41：The preparation of compound 18a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 18
The yield of compound 1 in embodiment 24, gained compound 18a is 26%.
1H NMR(400MHz,CDCl3) δ 7.66 (d, J=8.2Hz, 2H), 7.56 (d, J=8.2Hz, 2H), 7.52-7.47
(m, 2H), 7.10 (dd, J=7.8,1.2Hz, 1H), 6.98 (td, J=7.6,1.2Hz, 1H), 6.91-6.86 (m, 2H), 6.71
(dd, J=7.7,1.0Hz, 1H), 5.03 (s, 1H), 3.48 (s, 4H), 2.51 (s, 4H), 2.33 (s, 3H)
Embodiment 42：The preparation of compound 19a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 19
The yield of compound 1 in embodiment 24, gained compound 19a is 33%.
1H NMR(400MHz,CDCl3) δ 7.55-7.42 (m, 2H), 7.37 (d, J=8.1Hz, 2H), 7.25-7.21 (m,
2H), 7.11 (dd, J=7.8,1.3Hz, 1H), 6.98 (td, J=7.6,1.3Hz, 1H), 6.92-6.84 (m, 2H), 6.71
(dd, J=7.7,1.2Hz, 1H), 4.97 (s, 1H), 3.50 (s, 4H), 2.51 (s, 4H), 2.38 (s, 3H), 2.34 (s, 3H)
Embodiment 43：The preparation of compound 20a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 20
The yield of compound 1 in embodiment 24, gained compound 20a is 22%.
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=8.1Hz, 1H), 7.88-7.76 (m, 2H), 7.49 (t, J=
7.6Hz, 2H), 7.46-7.35 (m, 3H), 7.31 (d, J=6.8Hz, 1H), 7.15 (dd, J=7.7,0.8Hz, 1H), 7.02
(td, J=7.7,0.9Hz, 1H), 6.97-6.85 (m, 2H), 6.75 (d, J=7.6Hz, 1H), 5.05 (s, 1H), 3.53 (s,
4H),2.48(s,4H),2.29(s,3H).
Embodiment 44：The preparation of compound 21a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 21
The yield of compound 1 in embodiment 24, gained compound 21a is 24%.
1H NMR(400MHz,CDCl3)δ7.91–7.82(m,4H),7.64–7.58(m,3H),7.51–7.44(m,2H),
7.14 (dd, J=7.8,1.1Hz, 1H), 6.99 (td, J=7.7,1.1Hz, 1H), 6.93-6.86 (m, 2H), 6.72 (d, J=
7.6Hz,1H),5.04(s,1H),3.53(s,4H),2.52(s,4H),2.33(s,3H).
Embodiment 45：The preparation of compound 22a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 22
The yield of compound 1 in embodiment 24, gained compound 22a is 32%.
1H NMR(400MHz,CDCl3) δ 8.71 (d, J=2.2Hz, 1H), 8.53 (dd, J=4.8,1.4Hz, 1H),
7.74-7.69 (m, 1H), 7.47-7.42 (m, 2H), 7.30 (dd, J=7.9,4.8Hz, 1H), 7.07 (dd, J=7.8,
1.2Hz, 1H), 6.94 (td, J=7.6,1.2Hz, 1H), 6.90 (d, J=8.9Hz, 1H), 6.85 (td, J=7.5,1.4Hz,
1H), 6.70 (dd, J=7.7,1.0Hz, 1H), 5.21 (s, 1H), 3.46 (s, 4H), 2.51 (s, 4H), 2.31 (s, 3H)
Embodiment 46：The preparation of compound 23a
The present embodiment is reacted according to 24 identical method of embodiment, is differed only in, and is replaced with compound 23
The yield of compound 1 in embodiment 24, gained compound 23a is 30%.
1H NMR(400MHz,CDCl3) δ 8.60 (d, J=6.0Hz, 2H), 7.55-7.51 (m, 2H), 7.36 (dd, J=
4.6,1.5Hz, 2H), 7.08 (dd, J=7.8,1.4Hz, 1H), 6.96 (td, J=7.6,1.3Hz, 1H), 6.92 (d, J=
8.2Hz, 1H), 6.88 (td, J=7.5,1.5Hz, 1H), 6.71 (dd, J=7.7,1.2Hz, 1H), 5.20 (s, 1H), 3.52
(s,4H),2.60(s,4H),2.38(s,3H).
Experimental example
The present invention has carried out external inhibiting tumor cell screening active ingredients to obtained 2 compound of general formula.
1, test philosophy
Sulforhodamine B (Sulforhodamine B, SRB) colorimetric method, is mainly used to detect cell proliferative conditions.SRB
It is a kind of pink anionic dye, soluble easily in water, alkali that in acid condition can specifically with intracellular constitutive protein matter
Acidic amino acid combines；Absorption peak, light absorption value and the linear positive correlation of cell concentration are generated under 540nm wavelength, therefore can be used as cell
Several quantitative detections.
2, instrument, reagent, material and given the test agent
Instrument：Superclean bench, CO2Incubator, Multi-functional inverted microscope, centrifuge, automatic microplate reader, the culture of 96 holes
Plate.
Reagent：DMEM, 1640 culture mediums, dimethyl sulfoxide (DMSO) (DMSO), Sulforhodamine B (SRB).
Material (cell strain)：Human breast cancer cell BCAP37, gastric carcinoma cells SGC7901, human liver cancer cell HepG2, people
Cervical cancer cell HeLa, human acute myeloid leukaemia HL-60.
Given the test agent：The compound 1a-23a of the application.
3, experimental method
Sample preparation：Take given the test agent DMSO dissolved compounds, ultrasonic dissolution, concentration 100mM/L, gained drug solution
It can be stored under the conditions of -20 DEG C.
The SRB of above-mentioned cell is tested：Human breast cancer cell BCAP37, gastric carcinoma cells SGC7901, human liver cancer cell
HepG2, human cervical carcinoma cell HeLa, human acute myeloid leukaemia HL-60.
Logarithmic phase cell is collected, is inoculated into 96 porocyte culture plates, and various concentration drug solution to be measured is added.It is passing through
After crossing culture in 72 hours, 10% trichloroacetic acid is added, is cultivated 1 hour at 4 DEG C, is rinsed 5 times and is air-dried with tap water.It deposits
The cell survived dyes 20min by 0.4% (w/v) Sulforhodamine B at room temperature, is rinsed 5 times with 1% acetic acid.With
The Tris solution of 10mM has carried out the dissolving of solution, and the light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument 540nm.
4, experimental data computational methods
Inhibiting rate (%)=(no medicine cell control well A values average value-medication hole A values average value)/without medicine cell control well A
It is worth average value × 100%.
Activity Results are as follows：
Can see from the above antitumor activity result, the compound of the present invention 4a, 12a, 16a, 17a, 18a, 19a,
20a, 21a have significant cancer cell suppression activity.Especially compound 4a, 18a, 19a, 20a, 21a to human breast cancer cell,
Five kinds of gastric carcinoma cells, human liver cancer cell, human cervical carcinoma cell, human acute myeloid leukaemia cells have preferable suppression
Make use, compound 12a, 16a, 17a to human breast cancer cell, gastric carcinoma cells, human acute myeloid leukaemia this three
Kind cell has good inhibiting effect.The compound of the present invention can be applied in treatment and the relevant metabolic disease of malignant tumour
In.
Above the present invention is described in detail, by generality explanation and specific embodiment, in base of the present invention
On plinth, it is made some modifications or improvements, this will be apparent to those skilled in the art.Therefore, without departing from this
These modifications or improvements on the basis of spirit, belong to the scope of protection of present invention.
Claims (10)
1. a kind of Dibenzazepines compound, which is characterized in that the Dibenzazepines compound has such as general formula 1 or leads to
Structure shown in formula 2：
Wherein, R1Selected from methyl, hydrogen, chlorine or bromine, R2Selected from methyl or hydrogen；
R3Selected from hydrogen, chlorine, bromine, the phenyl for replacing or being unsubstituted, naphthalene or pyridine；The hydrogen being substituted by phenyl is respectively independent
Ground is by one or more substitutions in fluorine, chlorine, methyl, methoxyl group, itrile group or trifluoromethyl.
2. Dibenzazepines compound according to claim 1, which is characterized in that R1For hydrogen or bromine, R2For hydrogen；
R3For bromine, substituted phenyl, naphthalene or pyridine；The hydrogen being substituted by phenyl is each independently by fluorine, chlorine, methyl or three
One or more substitutions in methyl fluoride.
3. Dibenzazepines compound according to claim 1 or 2, which is characterized in that R1For hydrogen or bromine, R2For hydrogen；
R3For bromine, substituted phenyl or naphthalene；The hydrogen being substituted by phenyl contraposition is each independently by methyl or trifluoromethyl
One or two kinds of substitutions.
4. according to claim 1-3 any one of them Dibenzazepines compounds, which is characterized in that shown in the general formula 1
Structure is one or more in following compound：
Structure shown in the general formula 2 is one or more in following compound：
5. according to claim 1-3 any one of them Dibenzazepines compounds, which is characterized in that shown in the general formula 2
Structure is selected from compound shown in 4a, 12a, 16a, 17a, 18a, 19a, 20a, 21a.
6. the preparation method of claim 1-4 any one of them Dibenzazepines compounds, which is characterized in that 1 institute of general formula
Show the preparation course of compound and is as follows：
(1) using o-iodobenzoic acid as raw material, esterification is occurred into absolute ethyl alcohol in it and obtains o-iodobenzoic acid ethyl ester, by adjacent iodobenzene
Ethyl formate carries out graceful react in Wall with o-phenylenediamine or 3,4- dimethyl o-phenylenediamines and compound 1 or 2 is made respectively respectively；
Or further：
(2) it is raw material with the compound 1, itself and N- bromo-succinimides or two chlordantoins is subjected to electrophilic substitution reaction point
It Sheng Cheng not compound 3 or 4-6；In the compound 4-6, R1Selected from hydrogen, chlorine or bromine, R3For chlorine or bromine；
Or further：
(3) it is raw material with the compound 3, by itself and R3-(BOH)2It carries out Suzuki reactions and generates compound 7-23 respectively；Institute
It states in compound 7-23, R3For the phenyl, naphthalene or pyridine for replacing or being unsubstituted；The hydrogen being substituted by phenyl is respectively independent
Ground is by one or more substitutions in fluorine, chlorine, methyl, methoxyl group, itrile group or trifluoromethyl.
7. the preparation method of claim 1-5 any one of them Dibenzazepines compounds, which is characterized in that
The preparation course of compound shown in general formula 2 is as follows：
Specially：Compound shown in general formula 1 carries out chlorination with phosphorus oxychloride and generates imino group chloride, by gained imino group
Chloride reacts to obtain compound shown in general formula 2 with excessive N methyl piperazine；
Wherein, R1、R2And R3Reference with described in any one of claim 1-5.
8. application of the Dibenzazepines compound as inhibition of cancer cell agent described in any one of claim 1-5.
9. application according to claim 8, which is characterized in that the wherein described cancer cell is breast cancer cell BCAP37, people
Gastric carcinoma cell line SGC-7901, human liver cancer cell HepG2, human cervical carcinoma cell HeLa or human acute myeloid leukaemia HL-
60。
10. application of the Dibenzazepines compound in preparing treating cancer drug described in any one of claim 1-5,
The cancer is preferably breast cancer, gastric cancer, liver cancer, cervical carcinoma or leukaemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711462414.6A CN108586364B (en) | 2017-12-28 | 2017-12-28 | Dibenzoazepine compound and preparation method and application thereof |
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| CN110183387A (en) * | 2019-05-09 | 2019-08-30 | 新乡医学院 | Dibenzo diaza * ketone derivatives with anticancer activity and its preparation method and application |
| CN114702454A (en) * | 2022-03-29 | 2022-07-05 | 江西师范大学 | Preparation method of 5-alkyl-11-aryl-5H-dibenzo [ b, e ] [1,4] diazepine derivative |
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| CN114702454A (en) * | 2022-03-29 | 2022-07-05 | 江西师范大学 | Preparation method of 5-alkyl-11-aryl-5H-dibenzo [ b, e ] [1,4] diazepine derivative |
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